Senomorphic Development to Reduce the Senescence Associated Secretory Phenotype
The burden of cellular senescence increases with age, perhaps largely because the immune system becomes less able to remove senescent cells in a timely fashion. Lingering senescent cells are significantly harmful even when making up one percent or less of all cells in a tissues. This is because cells in a senescent state vigorously generate a mix of pro-growth, pro-inflammatory signals, the senescence-associated secretory phenotype (SASP). The SASP changes cell behavior for the worse, encourages chronic inflammation, and induces nearby cells to also become senescent. This is actively disruptive to tissue function, and contributes directly to the pathology of many age-related conditions.
Much of the medical research and development relating to senescent cells is focused on finding ways to selectively destroy them, the production of senolytic drugs. However, a sizable faction within the research community are interested in instead minimizing or blocking some or all of the SASP, the production of senomorphic drugs. This seems less beneficial as a strategy, since the SASP is not fully mapped, and treatments would have to be continual rather than intermittent, but some researchers are concerned that removal of senescent cells in some tissues may cause harm. To me, that seems to have been already demonstrated a lesser concern, given the evident, lasting benefits produced in mice following clearance of senescent cells.
Today's open access review paper makes the point that the development of senomorphic drugs remains at a very rudimentary stage in comparison to senolytic development. Too little is known of the SASP and its regulation, and too little is known of what exactly the initially identified senomorphic compounds actually do to the SASP. Researchers typically measure levels of a few of the better known pro-inflammatory SASP proteins in order to gain some idea of the effects of a candidate senomorphic drug, but the SASP likely consists of hundreds of different molecules. A great deal of work lies ahead.
Given the importance of senescence in physiological processes, it is reasonable to think that there is a threshold beyond which the accumulation of senescent cells induces a microenvironment conducive to the development of pathologies via SASP. The accumulation of senescent cells can also occur when the immune system ages, altering the ability of immune cells to clear senescent cells. Elimination of senescent cells by senolytics demonstrated a contributive role of senescent cells in ageing and age-related diseases and paved the way for the development of senotherapeutic approaches. Therefore, over the past 5 years, senotherapeutic research has emerged to slow down the ageing phenotypes. Current senotherapeutic strategies targeting senescent cells are mainly based on drugs that specifically kill senescent cells (senolytics) and components that suppress the detrimental effects of SASP without inducing senescent cell death (senomorphics, also known as senostatics).
We will not cover all senotherapeutic strategies, especially as excellent reviews have recently been published on senolytic developments, but rather focus on those with senomorphic activities, based on their ability to block SASP components.
A first strategy would consist in using neutralizing antibodies, recognizing and blocking specific surface proteins upregulated at senescence. Secretion of IL-6 has been decreased in senescent HUVECs and fibroblasts treated with anti-TNFα or anti-ephrin B2 antibodies, respectively. Several other surface proteins are known to play a role in the regulation of SASP profiles, including SCAMP4, Notch, and CD36. However, it has not yet been reported that the use of neutralizing antibodies targeting SCAMP4, Notch, or CD36 can impact the composition of SASP and, therefore, arrive at a conclusion regarding their senomorphic properties. In a model of bleomycin-induced senescence, the secretion of certain SASP factors (including IL-6 and IL-8) can be directly inhibited with neutralizing antibodies such as those against the membrane-bound IL-1α. It would be interesting to investigate the impact of other neutralizing antibodies directed against other major SASP factors such as circulating IL-1β-, IL-6, or their receptors, on their abilities to alter the chemical composition of SASP, impair SASP-mediated effects, and attenuate other features of senescence in different cell types.
A second strategy would be to use pharmacological and natural compounds. Many senomorphics are polyphenols (including flavonoids, phenolic acids and lignans) that possess antioxidant activities, but their modes of action have not been thoroughly studied. Other senomorphics are plant extracts consisting of a mixture of terpenes, alkaloids, and polyphenols. The biological effects of these compounds are multiple, ranging from the activation of antioxidant enzymes to the reduction in interleukin or MMP expression, and the inhibition of MAPKs. Most senomorphics modulate the senescent phenotypes to disrupt the proinflammatory nature of senescent cells.
Most studies, however, have only assessed a few SASP major factors (such as IL-6, IL-1β, and MMPs) following senomorphic treatments, which is not representative of SASP as a whole. Moreover, the impact of senomorphics on the secretion of extracellular matrix components, microvesicles, and complex lipids remains largely unexplored. Senomorphics can act on multiple targets depending on the context, the nature, and the model of senescence. In some cases, we cannot rule out that they might even increase the secretion of some detrimental factors. This raises the concern that SASP resulting from senomorphic treatment should probably be less deleterious and should be considered as modified rather than non-senescent-like. In addition, few studies are using conditioned media from senescent cells treated with senomorphics to examine the biological effects of the modified SASP (such as the pro-tumoral impact or differentiation) on other cell types. In the absence of more extensive data, it is difficult to assess the real effectiveness of senomorphics on SASP.